Lifestyle factors, such as diet, exercise, cognitive enrichment, and social stimulation are related to the risk of acquiring Alzheimer's disease (AD) and the severity of the symptoms. Furthermore, in both clinical studies and in studies in transgenic mouse models of AD, these factors have also often been shown to improve aspects of the symptoms. However, standard rodent environmental enrichment paradigms are not well suited for teasing apart the potential therapeutic aspects, but a method for providing a progressively challenging, sustained and cognitive-specific training regimen to mice would be able to study the cognitive challenge specifically (hereafter referred to as Progressive Cognitive Stimulation or PCS). It is unknown how such a sustained complex cognitive challenge might impact specific cerebral amyloid pathologies, associated neuroinflammation, and performance on the potential for new learning. Furthermore, how this complex cognitive challenge compares to a classic methodology, home-cage environmental enrichment (EE), is likely to be very revealing of the relative impacts of task-specific (PCS) versus general environmental complexity (EE). Accordingly, the hypotheses of our proposal are 1) PCS may ameliorate cerebral pathologies and preserve spatial learning and memory performance, and 2) PCS and the classic EE approach will interact by acting on multiple aspects of pathology. To test these hypotheses, it will first be determined if PCS reduces cerebral amyloid associated pathologies and preserves spatial learning and memory ability in transgenic Tg-5xFAD mice. Next, it will be determined how PCS compares to home-cage EE to determine whether a combination of these methodologies is required to achieve maximal benefits and whether they have different impacts on pathology. A well-characterized transgenic mouse model will be employed to investigate the differential contributions of cerebral microvascular amyloid and parenchymal amyloid to impairments of standard and complex learning and memory tasks. The established Tg-5xFAD mouse is a model of early-onset and robust parenchymal amyloid accumulation. Tg-5xFAD mice exhibit plaque-associated neuroinflammation and develop behavioral impairments. These studies intend to address important and timely questions including: Does long term cognitive-specific stimulation, through PCS, provide protection from amyloid pathologies and preserve new learning of spatial tasks? Completion of these studies will provide valuable insight into how different cognitive interventions impact on amyloid pathologies.